Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2 hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

Effects of Midazolam/Dexmedetomidine with Buprenorphine or Extended-release Buprenorphine Anesthesia in C57BL/6 Mice.

The effects of commonly used injectable combinations of anesthetics such as ketamine and xylazine, with or without acepromazine, vary widely across individuals, have a shallow-dose response curve, and do not provide long-term analgesia. These drawbacks indicate the importance of continuing efforts to develop safe and effective injectable anesthetic combinations for mice. In this study, a series of experiments was designed to validate the use of dexmedetomidine and midazolam to provide chemical restraint for nonpainful procedures and the addition of buprenorphine or extended-release buprenorphine to reliably provide a surgical plane of anesthesia in C57BL/6J mice. Loss of consciousness was defined as the loss of the righting reflex (LORR); a surgical plane of anesthesia was defined as the LORR and loss of pedal withdrawal after application of a 300 g noxious stimulus to a hind paw. The combination of intraperitoneal 0.25 mg/kg dexmedetomidine and 6 mg/kg midazolam produced LORR, sufficient for nonpainful or noninvasive procedures, without achieving a surgical plane in 19 of 20 mice tested. With the addition of subcutaneous 0.1 mg/kg buprenorphine or 1 mg/kg buprenorphine-ER, 29 of 30 mice achieved a surgical plane of anesthesia. The safety and efficacy of the regimen was then tested by successfully performing a laparotomy in 6 mice. No deaths occurred in any trial, and, when administered 1 mg/kg atipamezole IP, all mice recovered their righting reflex within 11 min. The anesthetic regimen developed in this study is safe, is reversible, and includes analgesics that previous studies have shown provide analgesia beyond the immediate postsurgical period. Buprenorphine-ER can be safely substituted for buprenorphine for longer-lasting analgesia.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Refinement of the motorised laminectomy-assisted rat spinal cord injury model by analgesic treatment.

Usage and reporting of analgesia in animal models of spinal cord injury (SCI) have been sparse and requires proper attention. The majority of experimental SCI research uses rats as an animal model. This study aimed to probe into the effects of some commonly used regimens with NSAIDs and opioids on well-being of the rats as well as on the functional outcome of the model. This eight-week study used forty-two female Wistar rats (Crl: WI), randomly and equally divided into 6 treatment groups, viz. I) tramadol (5mg/kg) and buprenorphine (0.05mg/kg); II) carprofen (5mg/kg) and buprenorphine (0.05mg/kg); III) carprofen (5mg/kg); IV) meloxicam (1mg/kg) and buprenorphine (0.05mg/kg); V) meloxicam (1mg/kg); and VI) no analgesia (0.5 ml sterile saline). Buprenorphine was administered twice daily whereas other treatments were given once daily for five days post-operatively. Injections were given subcutaneously. All animals underwent dental burr-assisted laminectomy at the T10-T11 vertebra level. A custom-built calibrated spring-loaded 200 kilodynes force deliverer was used to induce severe SCI. Weekly body weight scores, Rat Grimace Scale (RGS), and dark-phase home cage activity were used as markers for well-being. Weekly Basso Beattie and Bresnahan (BBB) scores served as markers for functionality together with Novel Object Recognition test (NOR) at week 8 and terminal histopathology using area of vacuolisation and live neuronal count from the ventral horns of spinal cord. It was concluded that the usage of analgesia improved animal wellbeing while having no effects on the functional aspects of the animal model in comparison to the animals that received no analgesics.

Sex specific effects of buprenorphine on adult hippocampal neurogenesis and behavioral outcomes during the acute phase after pediatric traumatic brain injury in mice.

Traumatic brain injury (TBI) in children often causes cognitive and mental dysfunctions, as well as acute and chronic pain. Adult hippocampal neurogenesis plays a key role in cognition, depression, and pain. Adult hippocampal neurogenesis can be modulated by genetic and environmental factors, such as TBI and opioids. Buprenorphine (BPN), a semisynthetic opioid, is commonly used for pain management in children, however, the effects of BPN on adult hippocampal neurogenesis after pediatric TBI are still unclear. This study investigated the sex-specific effects of BPN on adult hippocampal neurogenesis during acute phase after pediatric TBI. Male and female littermates were randomized on postnatal day 20-21(P20-21) into Sham, TBI+saline and TBI+BPN groups. BPN was administered intraperitoneally to the TBI+BPN mice at 30 min after injury, and then every 6-12 h (h) for 2 days (d). Bromodeoxyuridine (BrdU) was administered intraperitoneally to all groups at 2, 4, 6, and 8-h post-injury. All outcomes were evaluated at 3-d post-BrdU administration. We found that TBI induced significant cognitive impairment, depression, and reduced adult hippocampal neurogenesis in both male and female mice, with more prominent effects in females. BPN significantly improved adult hippocampal neurogenesis and depression in males, but not in females. We further demonstrated that differential expressions of opioid receptors, transcription factors and neuroinflammatory markers at the neurogenic niche might be responsible for the differential effects of BPN in males and females. In conclusion, this study elucidates the effects of BPN on adult hippocampal neurogenesis and behavioral outcomes at the acute phase after pediatric TBI.

Effect of transversus abdominis plane block with or without buprenorphine after inguinal hernia surgery on postoperative pain.

INTRODUCTION: Transversus abdominis plane (TAP) has been mentioned as having bene-ficial effects on chronic pain after hernioplasty. This study assessed the effects of TAP block on acute and persistent postoperative pain after inguinal hernia surgery, with or without buprenorphine. MATERIAL AND METHODS: 64 patients were allocated to group R ( n = 32) and received 20 mL of 0.25% ropivacaine for TAP block; group RB ( n = 32) received 20 mL of 0.25% ropivacaine containing 300 µg of buprenorphine for TAP block. The primary outcome was the analgesic and antihyperalgesic effect of buprenorphine. The duration of analgesia, analgesic consumption, postoperative pain scores at rest and sitting up to 48 hours, and the effect on wound hyperalgesia were evaluated. Secondary outcomes included the incidence of side effects and complications. RESULTS: The median (IQR) duration of analgesia in group R was 386.5 (37.25) minutes vs. 868 (41.3) minutes in the RB group. Median pain scores on sitting were found to be significantly better in group RB than in group R at 6, 12, and 24 hours ( P < 0.001). The wound hyperalgesia index showed a significant difference between groups ( P < 0.001). The incidence of persistent postoperative pain was 6.25% in the R group, as compared to 0% in the RB group. Otherwise, the patients did not have any further complications associated with the block. CONCLUSIONS: The results demonstrated that TAP block with buprenorphine reduced acute postoperative pain severity, but we did not find a difference between groups in persistent pain.

Effects of Extended-Release Buprenorphine on Mouse Models of Influenza.

Mice are widely used as small animal models for influenza infection and immunization studies because of their susceptibility to many strains of influenza, obvious clinical signs of infection, and ease of handling. Analgesia is rarely used in such studies even if nonstudy effects such as fight wounds, tail injuries, or severe dermatitis would otherwise justify it because of concerns that treatment might have confounding effects on primary study parameters such as the course of infection and/or the serological response to infection. However, analgesia for study-related or -unrelated effects may be desirable for animal welfare purposes. Opioids, such as extended-release buprenorphine, are well-characterized analgesics in mice and may have fewer immune-modulatory effects than other drug classes. In this study, BALB/c and DBA/2 mice were inoculated with influenza virus, and treatment groups received either no analgesics or 2 doses of extended-release buprenorphine 72 h apart. Clinical signs, mortality, and influenza-specific antibody responses were comparable in mice that did or did not receive buprenorphine. We therefore conclude that extended-release buprenorphine can be used to alleviate incidental pain during studies of influenza infection without altering the course of infection or the immune response.

Peripheral nerve block adjuncts: which medication to choose? A narrative review of the current literature.

Enhancing the effect of peripheral nerve blockade by adding other classes of medications has long history of trial and error. Studies have identified multiple potentially beneficial adjuncts that work to either speed the onset of analgesia or prolong its duration. The benefits of these adjuncts must be weighed against the risks of systemic negative side effects. To date, the most commonly used adjuncts, and ones with the most robust scientific efficacy are, dexamethasone, dexmedetomidine and buprenorphine. This narrative review will discuss several classes of local anesthetic adjuncts and provide evidence for the clinical efficacy and side effect profile of the most commonly studied medications.

A practical guide for buprenorphine initiation in the primary care setting.

Buprenorphine is a safe and effective treatment for opioid use disorder but remains underutilized because a major challenge of conventional buprenorphine initiation (termed induction) is that the patient must already be in opioid withdrawal. Previous legal barriers and clinician lack of familiarity with the unique pharmacology of buprenorphine have also limited its use. In this review, we outline changes regarding buprenorphine prescribing laws and physician perceptions of buprenorphine. We also review buprenorphine pharmacology and novel low-dose buprenorphine induction procedures that can be adopted in primary care settings to improve treatment acceptability, retention, and outcomes.

The efficacy of buprenorphine on moderate traumatic brain injury in the rat model.

INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of death, disability, and mental health disorders. A wide range of bioactive lipids, cytokines, and chemokines drives the inflammatory response. This study aimed to assess the efficacy of buprenorphine on moderate Trauma Brain Injury (mTBI) in rats. METHODS: In this study, 21 Wistar male rats weighing 230 ± 10 g were included. We trained cases by Morris water navigation task and mTBI induced by the pendulum. Then, buprenorphine treatment with 0.05 mg per kilogram of body weight continued from day 8 to 21. Finally, by Micro-Computed Tomography, behavioral evaluation by the Morris aqueous riddle test and biochemical factors of inflammation were assessed. RESULTS: Severe subdural inflammation was more in the treatment group than in the control group. The behavior of Rats showed that in the buprenorphine group, the mean duration of finding the platform increased compared to the control and Sham groups. However, the groups had no significant differences (P > 0.05). Biochemically, buprenorphine increased prolactin and decreased cortisol compared to the control and trauma groups (P < 0.05). CONCLUSION: These results suggest that buprenorphine causes fewer changes in behavioral functions in rats' models of mTBI and, because of their positive effect changes on inflammation biomarkers, biochemical behavioral tests, and CT scan images, could be ideal analgesic agents for pre-clinical responses after TBI.

Buprenorphine and methadone differentially alter early brain development in human cortical organoids.

Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a µ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are µ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications.

Subcutaneous administration of hydromorphone (0.2 mg/kg) provides antinociception in ferrets (Mustela putorius furo).

OBJECTIVE: To evaluate antinociceptive efficacy of SC administration of hydromorphone hydrochloride and buprenorphine hydrochloride in ferrets (Mustela putorius furo). ANIMALS: 14 healthy adult ferrets (6 neutered males, 8 spayed females). METHODS: In a randomized, blind, controlled, complete crossover design, all 14 ferrets received a single, SC injection of hydromorphone low dose (0.1 mg/kg), hydromorphone high dose (0.2 mg/kg), buprenorphine low dose (0.02 mg/kg), buprenorphine high dose (0.04 mg/kg), or saline solution (0.2 mL/kg). Sedation and forelimb withdrawal latency from a noxious thermal stimulation were evaluated, and behavior was recorded for a total of 8 hours postinjection. RESULTS: Compared to saline, administration of hydromorphone at 0.2 mg/kg resulted in an estimated increase of withdrawal latencies of 7.4 seconds (95% CI, 3.2 to 11.6) at 60 minutes, of 6.6 seconds (2.4 to 10.8) at 90 minutes, of 6.0 seconds (1.8 to 10.2) at 120 minutes, of 7.0 seconds (2.9 to 11.1) at 180 minutes, and of 4.5 seconds (0.5 to 8.6) at 240 minutes. These differences were statistically significant. Hydromorphone administered at a lower dose and buprenorphine at either dose did not increase withdrawal latencies compared to saline. Based on the sedation score used in this study, signs of sedation increased over time in a similar fashion with all treatments, including saline. Erratic dysphoric-like behaviors occurred in all groups except for saline. CLINICAL RELEVANCE: SC administration of hydromorphone at a dose of 0.2 mg/kg provided antinociception from 1 to 4 hours postinjection. Further validation of sedation scores in ferrets is warranted.

Buprenorphine reduces somatic withdrawal in a mouse model of early-life morphine exposure.

The rising prevalence of early-life opioid exposure has become a pressing public health issue in the U.S. Neonates exposed to opioids in utero are at risk of experiencing a constellation of postpartum withdrawal symptoms commonly referred to as neonatal opioid withdrawal syndrome (NOWS). Buprenorphine (BPN), a partial agonist at the mu-opioid receptor (MOR) and antagonist at the kappa-opioid receptor (KOR), is currently approved to treat opioid use disorder in adult populations. Recent research suggests that BPN may also be effective in reducing withdrawal symptoms in neonates who were exposed to opioids in utero. We sought to determine whether BPN attenuates somatic withdrawal in a mouse model of NOWS. Our findings indicate that the administration of morphine (10mg/kg, s.c.) from postnatal day (PND) 1-14 results in increased somatic symptoms upon naloxone-precipitated (1mg/kg, s.c.) withdrawal. Co-administration of BPN (0.3mg/kg, s.c.) from PND 12-14 attenuated symptoms in morphine-treated mice. On PND 15, 24h following naloxone-precipitated withdrawal, a subset of mice was examined for thermal sensitivity in the hot plate test. BPN treatment significantly increased response latency in morphine-exposed mice. Lastly, neonatal morphine exposure elevated mRNA expression of KOR, and reduced mRNA expression of corticotropin-releasing hormone (CRH) in the periaqueductal gray when measured on PND 14. Altogether, this data provides support for the therapeutic effects of acute low-dose buprenorphine treatment in a mouse model of neonatal opioid exposure and withdrawal.

Nano-invasomes for simultaneous topical delivery of buprenorphine and bupivacaine for dermal analgesia.

Opioid and local anaesthetic receptors are abundantly concentrated in different layers of the skin. Therefore, simultaneous targeting of these receptors can produce more potent dermal anaesthesia. Herein, we developed lipid-based nanovesicles for the co-delivery of buprenorphine and bupivacaine to efficiently target skin-concentrated pain receptors. Invasomes incorporating two drugs were prepared by ethanol injection method. Subsequently, the size, zeta potential, encapsulation efficiency, morphology, and in-vitro drug release of vesicles were characterized. Ex-vivo penetration features of vesicles were then investigated by the franz diffusion cell on the full-thickness human skin. Wherein, it was demonstrated that invasomes penetrated the skin deeper and delivered bupivacaine more effectively than buprenorphine to the target site. The superiority of invasome penetration was further evidenced by the results of ex-vivo fluorescent dye tracking. Estimation of in-vivo pain responses by the tail-flick test revealed that compared with the liposomal group, the group receiving invasomal formulation and drug-free invasomal formulation (only containing menthol) displayed increased analgesia in the initial times of 5 and 10 min. Also, no signs of oedema or erythema were observed in the Daze test in any of the rats receiving the invasome formulation. Finally, ex-vivo and in-vivo assays demonstrated efficiency in delivering both drugs into deeper layers of skin and exposing them to the located pain receptors, which improves the time of onset and the analgesic effects. Hence, this formulation appears to be a promising candidate for tremendous development in the clinical setting.

Role of efficacy as a determinant of locomotor activation by mu-opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR-selective phenylmorphans with high-to-low MOR efficacy.

Low-efficacy mu-opioid receptor (MOR) agonists represent promising therapeutics, but existing compounds (e.g., buprenorphine, nalbuphine) span a limited range of low MOR efficacies and have poor MOR selectivity. Accordingly, new and selective low-efficacy MOR agonists are of interest. A novel set of chiral C9-substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high-to-low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand-stimulated [35 S]GTPÉ£S binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high-efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower-efficacy MOR agonists. In the ligand-stimulated [35 S]GTPÉ£S binding assay, seven phenylmorphans had graded levels of sub-buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and ≥1 h duration of effects, evidence for MOR mediation, and minor sex differences. Tianeptine functioned as a high-efficacy MOR agonist. Overall, these in vitro and in vivo studies support the characterization of these compounds as MOR-selective ligands with graded MOR efficacy and utility for further behavioral studies in mice.

Comparisons of stress-related neuronal activation induced by restraint in adult male rat offspring with prenatal exposure to buprenorphine, methadone, or morphine.

Prenatal opioid exposure may impede the development of adaptive responses to environmental stimuli by altering the stress-sensitive brain circuitry located at the paraventricular nucleus of the hypothalamus (PVH) and locus coeruleus (LC). Corticotropin-releasing factor (CRF) released from neurons in the PVH has emerged as a key molecule to initiate and integrate the stress response. Methadone (Meth) and buprenorphine (Bu) are two major types of synthetic opioid agonists for first-line medication-assisted treatment of opioid (e.g., morphine, Mor) use disorder in pregnant women. No studies have compared the detrimental effects of prenatal exposure to Meth versus Bu on the stress response of their offspring upon reaching adulthood. In this study, we aimed to compare stress-related neuronal activation in the PVH and LC induced by restraint (RST) stress in adult male rat offspring with prenatal exposure to the vehicle (Veh), Bu, Meth, or Mor. CFos-immunoreactive cells were used as an indicator for neuronal activation. We found that RST induced less neuronal activation in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. RST-induced neuronal activation was completely prevented by central administration of a CRF receptor antagonist (α-helical CRF9-41, 10 µg/3 µL) in all exposure groups, suggesting the crucial role of CRF in this stress response. In offspring without RST, central administration of CRF (0.5 µg/3 µL)-induced neuronal activation in the PVH and LC. CRF-induced neuronal activation was lessened in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. Moreover, RST- or CRF-induced neuronal activation in the Meth exposure group was comparable with that in the Mor exposure group. Further immunohistochemical analysis revealed that the Meth and Mor exposure groups displayed less CRF neurons in the PVH of offspring with or without RST compared with the Bu or Veh groups. Thus, stress-induced neuronal activation in the PVH and LC was well preserved in adult male rat offspring with prenatal exposure to Bu, but it was substantially lessened in those with prenatal exposure to Meth or Mor. Lowered neuronal activation found in the Meth or Mor exposure groups may be, at least in part, due to the reduction in the density of CRF neurons in the PVH.

In Vitro-In Vivo Correlation of Buprenorphine Transdermal Systems Under Normal and Elevated Skin Temperature.

PURPOSE: Application of external heat using a heating pad over buprenorphine transdermal system, Butrans® has been shown to increase systemic levels of buprenorphine in human volunteers. The purpose of this study was to perform in vitro permeation studies at normal as well as elevated temperature conditions to evaluate the correlation of in vitro data with the existing in vivo data. METHODS: In vitro permeation tests (IVPT) were performed on human skin from four donors. The IVPT study design was harmonized to a previously published clinical study design and skin temperature was maintained at either 32 ± 1 °C or 42 ± 1 °C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on human skin were able to demonstrate heat induced enhancement in flux and cumulative amount of drug permeated from Butrans® which was reasonably consistent with the corresponding enhancement observed in vivo. Level A in vitro-in vivo correlation (IVIVC) was established using unit impulse response (UIR) based deconvolution method for both baseline and heat arms of the study. The percent prediction error (%PE) calculated for AUC and Cmax values was less than 20%. CONCLUSIONS: The studies indicated that IVPT studies performed under the same conditions as those of interest in vivo may be useful for comparative evaluation of the effect of external heat on transdermal delivery system (TDS). Further research may be warranted to evaluate factors, beyond cutaneous bioavailability (BA) assessed using an IVPT study, that can influence plasma exposure in vivo for a given drug product.

Efficacy and Safety of Buprenorphine in a Single-Shot Peripheral Nerve Block: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The purpose of this study was to evaluate the safety and efficacy of buprenorphine compared with placebo in prolonging the duration of analgesia in single-injection peripheral nerve block. The systematic review and meta-analysis were conducted following the PRISMA statement and Review Manager was used for meta-analysis. Outcomes were calculated using the mean difference (MD) with 95% confidence interval (CI) for continuous data. For dichotomous outcomes, effect sizes were estimated by calculating pooled risk ratio (RR) with 95% CI. Statistical heterogeneity was estimated by the I2 statistic. Compared with placebo, buprenorphine prolonged the duration of analgesia by an average of 8 hours (MD, 8.01; 95% CI, 6.79 to 9.24; P < .00001). The cumulative pain scores within 24 hours (MD, -0.8; 95% CI, -1.21 to -0.40; P < .0001) and the 24-hour opioid consumption (MD, -5.56; 95% CI, -10.60 to -0.52; P = .03) after surgery was lower with buprenorphine group. Conversely, buprenorphine increased the incidence of postoperative nausea and vomiting (PONV) (RR, 1.67; 95% CI, 1.16 to 2.39; P = .006). Buprenorphine is effective in prolonging analgesia, decreasing pain scores and opioid consumption, however, it increases the risk of PONV.